1. Field of the Invention
The present invention is directed to certain N-6 substituted adenosine derivatives which have beneficial cardiovascular activity in mammals, including humans and domestic animals.
2. Brief Description of the Prior Art
Cardiovascular activities of adenosine, and of certain of its derivatives, have been known in the art. German Offenlegungschrift Nos. 2133273, 2426682, 1795761, 1913818, 2007273, 2238923, 2060189, 2244328, 1814711, 2136624, South African Patent Application No. 677630 (filed Dec. 20, 1967) and British Patent Specification No. 1,123,245 describe adenosine derivatives which have cardiovascular, coronary dilator or antilipolytic activities.
In an article titled "Coronary Vasoactivity of Adenosine in the Conscious Dog" Olsson et al. describe a bioassay of compounds for cardiovascular activity. In the assay, the compounds to be tested are infused intracoronarily into conscious, healthy dogs. The naturally occurring nucleoside adenosine has a demonstrable coronary dilator effect under these conditions. The concentration of the test compound infused into the dog's heart, which causes half-maximal coronary vasodilation is designated ED.sub.50.
More specifically, under the conditions of this assay, ED.sub.50 is determined in the following manner. Late diastolic coronary conductance (LDCC of the experimental dog is monitored through suitable instrumentation. Late diastolic coronary conductance is measured at maximum coronary vasodilation (peak reactive hyperemia), and is designated LDCC.sub.max. Late diastolic coronary conductance is also measured at basal coronary vasodilation, and is designated LDCC.sub.o.
The difference between instantaneously measured late diastolic coronary (LDCC) and basal late diastolic coronary conductance (LDCC.sub.o) is expressed as a fraction of the difference between maximum late diastolic coronary conductance (LDCC.sub.max) and basal late diastolic coronary conductance (LDCC.sub.o). Thus .DELTA.LDCC is defined by Equation I. ##EQU1##
As the concentration of the tested compound is varied, and the corresponding .DELTA.LDCC is obtained through measurements and the above-summarized calculations, data of an ".DELTA.LDCC versus concentration" function or plot are obtained.
ED.sub.50 is derived from these data by log-logit transformation of the ".DELTA.LDCC versus concentration" plot; namely by solving the linear regression of logit (.DELTA.LDCC) on log (concentration) for .DELTA.LDCC=0.5.
ED.sub.50 of tested compounds was found to provide good comparison with data of the same or another compound tested on a different experimental dog, when the ED.sub.50 of the particular compound is related to ED.sub.50 of adenosine in the same experimental dog. As is set forth in Equation II, molar potency ration (MPR) is defined as the ratio of ED.sub.50 of adenosine to ED.sub.50 of the test compound. Molar potency ration (MPR) is a useful measure of cardiovascular vasodilatory effect, and hence of the utility of the tested compound. ##EQU2##
It follows from the foregoing, that the greater is the vasodilatory effect of a tested compound, the larger is the corresponding molar potency ratio (MPR).
An article by J. W. Daly titled "Adenosine Receptors: Targets for Future Drugs", Journal of Medicinal Chemistry 25, 197 (1982) provides a summary of various theories regarding the physiological role of adenosine and of certain adenosine analogs, agonists and antagonists.
As the above referenced patents and articles demonstrate, the prior art has provided and tested a relatively large number of adenosine derivatives for cardiovascular, and vasodilatory activity. Nevertheless, such derivatives having optimal biological properties have remained an elusive goal for the prior art. As is known, optimal biological properties include significant activity, absence of undesirable side effects, and sufficient duration of the desired activity.
The present invention is a significant development in the search for such optimal compounds. Compounds of the present invention have a novel structure and possess significant cardiovascular activity thereby providing an array of cardiovascular, vasodilator agents from which compounds having optimal characteristics as drugs for a particular type of application, may be selected.